7-Alkyl-{66 {hu 3,5{b -steroids

ABSTRACT

Novel steroids of the class of 7-alkyl-3,5-androstadienes, estradienes and gonadienes are prepared which are useful as antiprogestational and antifertility agents.

United States Patent [1 1 Grunwell et a1.

[ 7-ALKYL-A -STEROIDS 22 Filed: Mar. 26, 1973 21 Appl. No.: 344,838

[52] US. Cl 260/397.5; 260/239.55 R; 260/239.55 C; 260/397.3;260/397.45;

[51] Int. Cl. C07C 167/00; C07C 169/00 [58] Field of Search MachineSearched Steroids 1 June 17, 1975 [56] References Cited UNITED STATESPATENTS 3,246,022 4/1966 Chinn 260/3975 3,351,639 11/1967 Allen et a1.260/3973 3,471,531 10/1969 Hughes et al.. 260/3973 3,522,281 7/1970Anner et a1 260/3975 3,553,213 1/1971 Oliver et al. 260/2395 PrimaryExaminerE1bert L. Roberts Attorney, Agent, or Firm-William J. Stein;Eugene O. Retter; George W. Rauchfuss, Jr.

[5 7 ABSTRACT Novel steroids of the class of 7-a1kyl-3,5-androstadienes, estradienes and gonadienes are prepared which are usefulas antiprogestational and antifertility agents.

5 Claims, N0 Drawings 1 7-ALKYL-A3'5-STEROIDS BACKGROUND OF THEINVENTION Progesterone is unique among the steroid hormones by virtue ofthe fact that its presence is essential with most female mammals,including women, for the maintenance of a successful pregnancy. A lossof interference with progesterone during the early stages of pregnancyprevents the continuation of gestation.

In women the typical menstrual cycle is 28 days with the onset ofmenstruation counted as day one. During the interval from day to day 12,follicle-stimulating hormone (FSH) from the pituitary gland stimulatesthe growth of the primordial follicles of the ovary with the result thatby day 12 of the cycle a mature Graafian follicle is ready to ruptureand release a mature ovum. In addition to the formation of an ovum, thefollicle also produces estrogen which stimulates the conversion of theuterine endometrium into a proliferative phase. On day 14 the ovum isreleased and the follicle is converted into a corpus luteum which inaddition to estrogen now produces progesterone. These two hormonesstimulate the endometrial growth of the uterine lining converting it byday 19 from its proliferative phase into its secretory stage.

The ovum is released into the Fallopian tube and may be subsequentlyfertilized within a period of from 12 to 24 hours. At about day 18 /2,the fertilized ovum enters the uterus and by day 21 /2 to day 24 /2 theovum or blastocyst nidates within the uterine lining and begins toimplant. This implantation process is completed with the establishmentof the fetal-placental circulation which occurs at about day 35. Inorder for successful implantation to occur, a properestrogen-progesterone balance is required. Subsequent to theimplantation period, rapid placental development occurs, and by day 70to day 75 the placenta produces all of the progesterone required tomaintain pregnancy. Thus, the removal of the corpus luteum prior to day70 results in a rapid drop in progesterone levels and the expulsion ofthe uterine contents during a menstrual bleed. However, if in a pregnantwoman the corpus luteum is removed 70 days after the onset ofmenstruation, pregnancy will continue.

Applicants have made the important discovery that compounds of thisinvention possess marked antiprogestational properties. Thus they areable to reduce fertility when administered without interfering withnormal ovulation. In this regard these compounds differ from thecontraceptive steroids of the prior art, which inhibit ovulation orwhich interfere with ovum transport by virtue of their progestationaland/or estrogenic properties.

Administration of the antiprogestational agents of the present inventionthroughout the normal mammalian menstrual cycle results in adesynchronization of the maturing uterine mucosa relative to the0vulation process, thereby preventing nidation or implantation of thefertilized ovum. In women the withdrawal of progesterone from aprogesterone-primed uterine endometrium results in menstrual bleeding.Thus, the

monthly administration of the instant antiprogestational agentsfollowing ovulation insures menstrual cyclicity.

DESCRIPTION OF PRIOR ART US. Pat. No. 3,522,281 represents the closestart known to applicants and disclosures A""7a-methylestradienes asestrogenic agents, antigonadotrophic agents and as ovulation inhibitors.Thus, the importance of these novel products antifertility agentsresides in their ability to inhibit ovulation. In contrast thereto,applicants have made the important discovery that the chemicallydistinct and novel compounds of the present invention have novelantiprogestational activity. Applicants have further discovered thatboth the novel compounds of this invention as well as the prior artcompounds described above are useful as antiprogestational agents inreducing the fertility of fertile females without inhibiting orinterfering with ovulation.

US. Pat. No. 3,246,022 describes certain 3-aryl-l7B-hydroxy-androsta-3,S-dienes and 3-aryl-l7B-hydroxyestra-3,5-dienes whichare stated to reduce edema formation associated with the inflammatoryresponse to tissue insult. Additionally the compounds described thereinare stated to share with estrone a capacity to inhibit uterine responseto progesterone. The compounds of the present invention taken as a wholeare all substituted in the 7-position of the steroid nucleus. Thus, theyare distinct chemical entities from those described in the prior art. Inaddition. there is no indication in the prior art that these compoundswhen administered to fertile mammals, mammels, including women, inhibitnidation or prevent implantation, thereby reducing fertility in suchfemales.

SUMMARY OF THE INVENTION This invention relates to new steroids, totheir preparation and to their use as pharmaceutical agents. Moreparticularly, the novel compounds of the present invention are 7-alkyl-A-unsaturated steroids useful as antiprogestational agents represented bythe general formula:

wherein R R R and R are each hydrogen or methyl;

R is selected from the group consisting of hydrogen,

chloro, bromo, lower alkyl having from I to 4 carbon atoms, phenyl,halophenyl, hydroxyphenyl, tolyl, and methoxyphenyl;

R is lower alkyl having from I to 3 carbon atoms;

R,- is selected from the group consisting of CH Cl-IOH and C=O;

R is selected from the group consisting of hydrogen, lower alkyl havingfrom 1 to 6 carbon atoms, lower alkenyl and lower alkynyl having from 2to 6 carbon atoms, lower alkenynyl and lower alkadiynyl having from 4 to6 carbon atoms;

R,, is selected from the group consisting of hydrogen,

alcyl having from 2 to 12 carbon atoms, 2-

3 tetrahydropyranyl, trimethylsilyl, l-cycloalkenyl having from to 8carbon atoms, 1- methoxycycloalky and l-ethoxy-cycloalkyl in which thecycloalkyl group has from 5 to 8 carbon atoms, and the groups R and ORwhen taken together are 0x0 or a cyclic acetal; and

R is selected from the group consisting of hydrogen,

methyl and ethyl with the proviso that when R and R are hydrogen, R R R3 and R cannot all be hydrogen at the same time.

In general the novel compounds of the present invention are prepared insolution from their corresponding 7-alkyl-4-en-3-ones,7-alkyl-4-en-3-ols and 7-alkyl-5- en-3-ols using a variety ofdehydrating reagents. halo/enolizing reagents and organolithium orGrignard reagents, and isolating the products therefrom.

This invention also relates to the discovery that the novel compoundsdescribed in formula (l), in addition to certain compounds described inthe prior art, are

useful in reducing the fertility of fertile females in a manner otherthan by ovulation inhibition. More particularly, this enlarged class ofcompounds is represented by the general formula: I

wherein R R R and R are each hydrogen or methyl;

R is selected from the group consisting of hydrogen,

chloro, bromo, lower alkyl having from I to 4 carbon atoms, phenyl,halophenyl, hydroxyphenyl, tolyl, and methoxyphenyl;

R is lower alkyl having from 1 to 3 carbon atoms;

R is selected from the group consisting of CH CHOH and C=O;

R is selected from the group consisting of hydrogen, lower alkyl havingfrom 1 to 6 carbon atoms, lower alkenyl and lower alkynyl having from 2to 6 carbon atoms, lower alkenynyl and lower alkadiynyl having from 4 to6 carbon atoms;

R,, is selected from the group consisting of hydrogen,

acyl having from 2 to 12 carbon atoms, 2- tetrahydropyranyl,trimethylsilyl, l-cycloalkenyl having from 5 to 8 carbon atoms, 1-methoxycycloalkyl and l-ethoxyeycloalkyl in which the cycloalkyl grouphas from 5 to 8 carbon atoms, and the groups R and OR when takentogether are 0x0 or a cyclic acetal; and

R is selected from the group consisting of hydrogen,

methyl and ethyl.

DETAILED DESCRIPTION OF THE INVENTION As illustrated in general formulal above, the novel compounds of the present invention all contain analkyl substituent in the 7 -position of the steroid nucleus. Thissubstituent consists of either the methyl, ethyl, propyl or isopropylgroups and may be present in either the a or ,B-configuration asindicated by the wave-like bond at the point of attachment.

The compounds of the present invention also have unsaturation in commonat both the 3 and 5-positions of the steroid nucleus. Consequently, allof these novel compounds can be named as either 7-alkyl-3,5-androstadienes. estradienes or gonadienes. It should be noted, however,that with respect to the 7-alkyl-3,5- estradienes, all must possess atleast a mono-substituent in one of the 1,3,4 or 6-positions of thesteroid nucleus, i.e., R R R and R cannot all be hydrogen.

The 3-position of the steroid nucleus is either unsubstituted orsubstituted with a halogen, aliphatic, phenyl or substituted phenylgroup. The usual halogen substituents at the 3-position include thechloro or bromo radieals. The aliphatic group present at the 3-positioncomprises a lower alkyl group having from I to 4 carbon atoms andincludes such groups as methyl, ethyl, propyl, butyl, isobutyl andt-butyl. A phenyl group when present can be either unsubstituted ormonosubstituted. The substituents on the phenyl nucleus include suchgroups as halogen, as represented by fluorine, chlorine and bromine, ora hydroxyl, methyl and methoxy group. Illustrative of compoundscontaining a substituted phenyl radical in the 3-position are: 7aethyl-3-(4-methoxyphenyl)estra-3,5-dien-l7B-ol and7a-ethyl-3-(3-chlorphenyl)androsta-3,5-dien-l7B-ol.

The compounds represented by formula (I) include derivatives in whichthe ll-position of the steroid nucleus, represented by the symbol R iseither unsubstituted or is substituted with a hydroxy or an oxo group.Illustrative of such compounds are: 7,8-methylandrosta- 3,5-dienl 7B-ol,7/3-methylandrosta-3 ,S-diene-l 1,8, l7B-diol,7B-methylandrosta-3,S-diene-1la, l7B-diol, and7B-methylandrosta-3,5-diene-l l,l7-dione.

As illustrated in formula (1) above, the compounds of the presentinvention can be either monosubstituted or disubstituted in thel7-position of the steroid nucleus, i.e., they may be l7B-and/orl7aderivatives. Thus, the l7a-position may be either substituted orunsubstituted. When substituted, the compounds of this invention aresubstituted with either a saturated or an unsaturated aliphatichydrocarbon chain having from I to 6 carbon atoms. Illustrative of suchgroups are straight or branched chain alkyl radicals, as for example,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isoamyl, n-pentyland n-hexyl. lllustrative of the alkenyl groups which may be present arethe vinyl, allyl, lbutenyl, l-pentenyl and l-hexenyl radicals.Illustrative of the alkynyl groups present are ethynyl, l-propynyl,l-butynyl, and l-hexynyl. Illustrative of the unsaturated conjugatedhydrocarbon radicals present are the groups l,3-butenynyl,1,3-pentenynyl, 1,3-butadiynyl and 2,4-hexadiynyl.

Substituents in the I7B-position include esters and ethers of the freealcohol. When R is hydrogen, the free alcohol is present, as forexample, the compound la,7a-dimethylestra-3 ,S-dien-l 7,8-01.

The acyl esters which are present are derived from hydrocarbon acylradicals having from 2 to 12 carbon atoms inclusively. The organic acylgroups include those of saturated and unsaturated aliphatic acids andaromatic acids such as acetic, propionic, butyric, isobutyric, valeric,isovaleric, caproic, caprylic, decanoic,

dodecanoic. acrylic. crotonic. c vclobutaneearlmsylie.cyclopentaneearboxylic. eyclopentenecarboxylic. cyclohexanecarboxylic.benxoic. toluic. naphthoic. ethylbcnzoie. phenylaeetic.naphthaleneaeetic. phenylvaleric, cinnamie, phenylpropionic.p-propyloxyphenylpropionic and p-butyloxyphenylacetic acid.

The compounds of this invention also include certain l7B-ethers. Suchethers include unsaturated cyeloalkane ethers having from 5 to 8 carbonatoms in which the unsaturation is present in a position alpha to theether oxygen. Illustrative otsuch unsaturated ethers are theI-cyclopentene. I-cyclohexene or I-cyelooetene radicals. Thecorresponding saturated cycloalkanes are also considered to be withinthe scope of this invention wherein the cycloalkane group is furthersubstituted with either a methoxy or an ethoxy radical at its point ofattachment. Illustrative substituted cycloalkanc ethers include:7a-ethyl-l7Bt l methoxyeyclopentyloxy)-estra-3.5-diene 7a-ethyl I 7B( I'-ethoxycyclohexyloxy )-estra-3.5-diene. 70!- methyl-I7fi( l'-methoxycycloheptyloxy)-estra-3,5- diene and 7a-methyI-I7B( l-ethoxycycltmctyloxy)- estra-3,5-diene. The 178- class ol ethers alsoincludes saturated heterocyelic ethers. illustratively. 3.7adimethyl-l7B-t 2'-tetrahydropyranyloxy )-androst-3,5- diene and la,7adimethyI-l7B-(2- tetrahydropyranyloxy)-estra-3.5-diene. Ethers such astrimethylsilyl ethers likewise fall within the purview of the presentinvention.

Both the I701 and l7B-positions may be combined to represent a ketone.Thus, the compounds of this invention include I 1 and/or l7-ketones. asfor example. 173- hydroxy. 'lfi-methylestra-Z.S-dien-l I-one. 7,8-methylcstra-3,S-dien-l7-one and 7/3-methylestra-3.5- diene-I l.l7-dione.

Additionally the 1701 and l7B-positions may be taken together to form aI.3-dioxolane or other cyclic acetal. Illustrative of such compounds are7a-propylandrosta- 3,5-dien-I7-one cycie I7-(ethylene acetal) and 3-chlore-7oz-methyl-estra-B,S-dien-l7-one cyclic l7- (ethylene acetal).

A preferred group of compounds is obtained when the 3-position of thesteroid nucleus contains a methyl substituent. the 7-position contains amethyl group in the a-configuration and the l7a-position of the steroidnucleus remains unsubstituted. i.e.. R is methyl, R is a a-methyl and Ris hydrogen. This group is illustrated by the formula:

R OR l lll wherein R R R,. R... R,.. R and R have the values previouslyassigned.

The following compounds further illustrate the species represented bygeneral formula (I) above: 17al'-butynyl )-3- I01.7a-dimethylandrosta-3.5-dien-I 7B- ol. la,7a-dimethyl-3'phenylandrosta-3.S-dien-l7B-ol butyratc.701,13-diethylgona-3.S-dien-17,8-ol. I3-ethyl- 7a,]7a-dimethylgonal-3.S-dien-l 7B-ol. 17,8-( 1 cycIopentenyloxy)-l3-ethyI-7a-methylgona-3,S-diene. 4.7a-dimethylestra3.5-dien-I7B-ol.3.7a-dimethyll7B-( l-methoxycyclohexyloxy)-estra-3.5-diene.3.7adimethyI-l7B( l cyclohexenyloxy)-estra3.5dienc. 3.7a, I7a-trimethyI-estra-3,S-dien- I 7Bol, 3,704,170!-trimethylestra-3.S-dien-I7B-ol heptanoate. 3.701.170!-trimethyIestra-3,S-dien-l 7B-ol propionate. 3,701-dimethylestra-3,5-dien-I 7-onc, 3.7oz-dimethyl- 1 7a( I propynyl)estra-3,5-dien- I 7/3-ol, 4,6,7atrimethylandrosta-3,S-dien-I7,B-ol,4,6.7atrimethyIandrosta-3.S-dien-l7B-ol dodecanoate, 111,6,-7a-trimethylandrosta-3,S-dien- I 7-onc. 7B-ethyI-3-phenylandrosta-3.S-dien- I 7B-ol. 7,8-ethyl-3-phenylandrosta-3,S-dien-I7B-ol decanoate. 3-methyl-7a-propyIandrosta-3,S-dienl 7-one. l7a-ethinyl-7amethyl-3(p-methoxyphenyl)-androst-3.5-dien-l 7,8-ol. 7B-ethyl-3t m-methoxyphenyl)-androsta-3,5-dien l7-one. 7a, 1 7a-dimethyl-3tp-fluorophenylJ-androsta- 3,5-dien-17B-ol. 7ot-methyl-3(p-fluorophenyU-estra-3.5-dien-I7-one, I01,7,8-dimethyl-3-phenylandrosta- 3.5-dien- I 7-one.4.7B-dimethylandrosta-3,S-dienl7-one, la4.7a-trimethyIandrosta-3,S-dien-I 7B-ol. 7a-

methyl-1 7a-vinyIandrosta-3 ,S-dien-l 7,8-ol, 3.7adimethyl- I7a-vinyl-estra-3.5-dien- I 7,8-0]. la,7adimethyl- 17a-vinylandrosta-3.S-dien- I 78-01 acetate,

and la,7a-dimethyl- I 7B-tetra-hydropyranyloxyandrosta-3,5-diene.

The compounds of the present invention are prepared by methods analogousto those in the art. The 3- chIoro-3.5-dienes are prepared by reacting aA"-3-keto steroid with at least one equivalent of a chloro/enolizingagent such as phosphouous oxychloride. prosphorous pentachloride oroxalyl chloride generally in the presence of an acid catalyst suchacetic acid, oxalic acid. p-toluene-sulfonic acid. Alternatively. theVilsmeier reagent. phosphorous oxychloride in dimethylformamide. may beemployed. The reaction proceeds at temperatures ranging from about 0 tol()()C.. although temperatures near room temperature are preferred.Suitable inert solvents include benzene, heptane, toluene.dimethylformamide and acetic acid. The 3-bromo-3,5-dienes are preparedin a similar fashion substituting a bromo/enolizing agent such asphosphorous tribromide or oxalyl bromide in the above procedure. In thismanner I7oz-ethinyl-l7/3-hydroxy-7amethyl-4-androsten-3-one acetate,I7B-hydroxy-7amethyI-4-estren-3-one acetate and l3-ethyl-l7B-hydroxy-7a-methyl-4-gonen-3-one acetate and converted in good yield to3-chloro-I7a-ethinyl-7amethyl-3,S-androstadien-I7B-ol acetate,3-bromo-7amethyl-3.5-estradien-l7B-ol acetate and 3-chloro-l3-ethyl-7a-methyl-3.S-gonadicn-l78-0] acetate. respectively.

The 3.5-dienes wherein R is hydrogen arc synthesized by eliminationofthe elements of water from a A- B-hydroxy or A -3-hydroxy steroid.Preferably. a A -3- hydroxy steroid is treated with an acid such ashydrochloric acid. p-toluenesulfonic acid. methanesulfonic acid,sulfuric acid or acetic acid is a solvent such as acetone. methanol.ethanol. dioxane or tetrahydrofuran. Water may also be utilized as aco-solvent and the temperature can vary from about C. to the refluxtemperature of the particular solvent employed. Alternatively, halidesof inorganic acids such as phosphorous oxy chloride and thionyl chloridein the presence of a tertiary amine such as triethylamine or pyridinemay be utilized to effect these dehydrations in such solvents as ether,dioxane or tetrahydrofuran. Basic reagents such as aluminum oxide arealso successfully employed to effect dehydration. The A -3-hydroxysteroids can be converted to the 3-tosylate .of 3-mesylate in the usualmanner by treatment with p-toluenesulfonylchloride ormethylsulfonylchloride in pyridine at 0C. Elimination of the tosylate ormesylatc is effected with alkaline reagents in neutral solvents such aspotassium t-butoxide in dimethylsulfoxide or lithium bromide and lithiumcarbonate in dimethylformamide. An ester residue can also be eliminatedby pyrolysis from the 3-xanthate. phenylcarbamate, ethylcarbonatederivatives of A' -3- ols to produce the desired 3,5-dienes. Using theseprocedures 7a-ethyl-3,5-androstadiene-l 7,B-ol. 7a, 170(-dimethyl-3,5-estradien-l7B-ol and 6,7a-dimethyl-3.5- androstadien-I7B-olare synthesized from "laethylandrost-4-en-3B,l7B-ol.7a,l70z-dimethyl-4-estrene- 35, 173-01, and6,7a-dimethylandrost-4-ene-3B, 1 7pdiol. respectively. y i

The preparation of the 3,5-dienes wherein R is lower alkyl or phenylproceeds by treating the corresponding 4-en-3-one with an appropriateorganometallic reagent, as for example, an organolithium reagent or aGrignard reagent. Anhydrous solvents such as ether or tetrahydrofuranare generally employed. The intermediate tertiary allylic alcohol whichforms. is subsequently dehydrated to form the 3-alkyl or 3-phenyl-3,5-

dicne. This dehydration is catalyzed by hydrogen ions.

as for example, hydrochloric acid, p-toluenesulfonic acid, acetic aeidinsuch solvents as acetone, methanol, ethanol, dioxane, tetrahydrofuranand aqueous mixtures thereof. The allylic alcohol intermediate may alsobe directly dehydrated without isolation by addition of the Grignardreaction mixtureto an aqueous mineral acid orby heating with acidicalumina in a solvent such as aqueous alcohol. Additionally thedehydration of the tertiary allylie alcohol may be affected by treatmentwith an acid halide and a tertiary base, as for example, phosphorusoxychloride andtriethylamine or pyridine, in in inert solvent such asether or dioxane. Following these procedures the compounds7a,l7a-dimethyl-3- (p-methoxyphenyl)-3,5estradiene-l7B-ol, 7B-ethyl-3-(p-chlorophenyl)-3,5-androsta-dien-l 713-01 and 3,6,7-a,l7oz-tetramethyl-3,S-androstadien-l7B-ol are obtained from701,17a-dimethyl-l7B-hydroxyestr4-en- 3-one,7B-ethyl-l7B-hydroxy-androst-4-en-3-one and6,7a-dimethyl-androst-4-ene-3,l7-dione, respectively.

The staring materials for the compounds of the present invention are7-alkyl-4-en-3-ones, 7-alkyl-4-en-3- ols and 7-alkyl-5-en-3-ols. Thesecompounds are best prepared from the corresponding 7-alkyl-5-en 3 onesavailable in good yield from the reaction of a ditlower alkyl) copperlithium with a 4,6-dien-3-one in an inert solvent such as ether.tetrahydrofuran, hexane or mixtures thereof at temperatures ranging from78 to 25C. The initially formed enolate anion is quenched by addition toa protonating agent such as saturated solution of ammonium chloride,oxalic acid or boric acid to provide the desired 7-alkyl-5-en-3-one.

The 7-alkyl-5-en-3-one is reduced to the 7-alkyl-5- en-3-ol by reducingagents such as sodium borohydride, lithium aluminum hydride and lithiumtri-ttutoxyaluminum hydride by procedures well known to alsobetreducedby reagents such as lithium aluminum hydride, lithiumtri-t-butoxy-aluminum hydride so- .dium borohydrideto form. thedesired7-alkyl-4'en-3! .01.

The.halo-3,5-dienes are preferably prepared .from

l7B hydroxy-4 en3-one, acylates; 1or 4-en13 l7-dione lTi-ketals whereasthe 3,5-dienes. .3-alkyl-3.5-dienes and 3-aryl-3.5-.dienes arepreferably obtained from intermediates containing a l 'l-ketal. or.a.free' I 7-hydroxy groups These various ketals, alcoholstand esters larereadily. removed,.,oxidized, reduced, -a'cylated, .alkylated andetherified using standard. methods known to i the art. For exainple..theketonercan beireadilytregenerated from thexketal under acid conditions.The ketone can be reduced to the'al'cohol bymetallo-hydride reagents"such as lithium aluminum hydride or sodium borohydride. The ketone canbe alkylated to form a :l 7a-alkyl. alkenyLor alkynyl 17B-ol by reactionwith an-appropriate organometallie;reagent. asrforexampleumethylmagnesium bromide or propinyl llithium. The free hydroxygroup may be acylated by means of an acid hal ide or acid anhydride inthe presence of a'tertiar y base such as pyridine. Suitable acidmoietiesinclude acetic, .propionic, decanoic and cyclohexane darboxylieacids. The tetrahydropyranyl ether is p'repared by the action ofdihydropyran in the presence of an acid catalyst such asp-toluenesulfonic acid or pho:phoro'us oxychloride witha3',5-dienl7B-ol. The l-alkoxycycloalkoxy derivatives of this inventionare prepared by reaction of a'3,5-diehl7B-ol'with a loweralkylk etal ofa cycloalkanone or the lower a]- 'kylen'olether of a cycloalkanone 'or amixture of these in the'presence of an. acid catalyst preferablypyridine ptoluenesulfonate in solvents such as dioxane, tbutanol, ormethylene chloride. Temperatures during the reaction can vary from about20 to C. with the lower temperatures preferred. Suitable cycloalkylderivatives include, for example, cyclopentanone diethylketal andl-methoxy-l-cyclohexene. Following essentially the same procedure butvarying the reaction solvents in order to obtain reaction temperaturesabove 70C., the l-cycloalkenylethers are directly prepared. Suitablesolvents include benzene and dimethylformamide. Alternatively, thel-cycloalkenylethers are prepared by pyrolysis of the isolatedl-alkoxycycloalkoxy steroid in the presence of a trace of an organicbase such a pyridine in a high boiling solvent such toluene. benzene.dimethylformarnide. The 3.5-dien-l7-ol is oxidized to the3,5-dien-l7-one by means of the op- -penauer reaction or thePfitzer-Moffatt procedure which utilizes dicyclohexylcarbodiimide,dimethylsulfoxide, pyridine and trifluoroacetic acid.

Applicants have discovered that the 7-alkyl-A"' steroids represented byformula (11) above possess antiprogestational activity. Administrationto fertile female mammals prior to the decline in ovarian dependence forprogesterone insures the absence of an'implanted ovum. In women theovarian/placental shift of progesterone synthesis occurs about 55 daysfollowing ovulation or on about day 70, if counted from the onset of thelast menstruation. By insuring the absence of an implanted ovum, estrusin fertile female mammals. or menstrual cyclicity in fertile femaleprimates, such as monkeys, baboons and humans, will occur.

The antiprogestational effect of the compounds represented by Formula ll is demonstrated by observing the decidual cell reaction of atraumatized uterine horn of an immature female rat receivingprogesterone. Traumatization of the uterine horn simulates apseudoimplantation. The increase in tissue weight of the traumatizedhorn in comparison to the untraumatized contralateral control uterinehorn, measures progesterone stimulated growth. Conversely, a reductionof this progesterone-primed decidual response is an in vivo biologicalmeasure of the antiporgestational activity of these compounds.

The effect of these compounds upon nidation and implantation isdemonstrated by their administration to pregnant hamsters at a pointimmediately and subsequent to nidation and observing their prepartumeffects. Mated female hamsters, considered to be pregnant by thepresence of sperm in a post-estrus vaginal levage, are treatedsubcutaneously with the test compound during days 38 of pregnancy. Thisperiod of gestation in the hamster relates from a point just prior toimplantation of a fertilized ovum to a point after which implantationhas occured and placental circulation is now complete. Treated animalsare sacrificed one day prior to parturition and the total number of livefeti is compared to those in a control group of mated female hamsters.

The term fertile female as used herein refers to any female mammal thatcan reproduce and that requires progesterone for reproduction andgestation. illustrative of such species are mice, rats, guinea pigs,rabbits, ferrets, dogs, cats, cows, horses and primates, includingmonkeys, baboons and humans.

The 7-alkyl-3,5-unsaturated steroids are variously administered in orderto achieve their antiprogestational effect. In women they areadministered prior to ovulation either daily to weekly in small doseswhich do not interfere with ovulation. When these agents areadministered in small doses, i.e., a mini-pill" type of regimen,fertility is inhibited without inhibiting or interfering with theovulatory process. Administered in this fashion, the maturation of theuterine lining is forced out of phase with the ovulation process,thereby preventing nidation or implantation of the fertilized egg.Alternatively, the 7-alkyl-3,5-unsaturated steroids are administered inone or more larger doses following ovulation, but prior to theoccurrence of the progesterone ovarian/placental shift, which takesplace approximately 55 days after ovulation. Such doses, administeredsubsequent to ovulation, halt further nidation or implantation. y

The onset of ovulation varies, of course, from species t species. Inwomen ovulation occurs on or about day or during the period from aboutday 14 to about of the menstrual cycle. After this period the placentaindependently supplies the necessary progesterone, and the instantcompounds are no longer significantly effective as antiprogestationalagents. Failure of the fertilized ovum to implant insures the lack offurther development into a mature fetus. in the higher primates thereresults a menstrual bleed which indicates the lack of pregnancy.

The contranidative effect of these 7-alkyl-3,5- unsaturated steroids canbe utilized to insure the failure of a fertilized ovum to implant in anyfertile female mammal as previously defined. Thus the present inventionis useful for reducing the fertility in such commercially valuablespecies as dogs, cats, cows and horses. Generally the compounds areadministered for a period of time not exceeding 50% of the gestationperiod for the particular species. Preferably the compounds areadministered during the first quarter of the gestation period.

The particular dosage of the active ingredient depends upon such factorsas the route of administration, age, weight of the mammal being treatedand the frequency of dosing. A post-ovulatory dosage unit of thetherapeutic steroid contains from about 0.1 milligrams to about 3.0grams of the active ingredient per administration with dosages repeatedas necessary. Dosage units administered prior to ovulation using amini-pill type of regimen contain from 0.1 mg to L0 mg, de pending uponthe particular steroid employed. Preferably a dosage unit of from 0.1 mgto 0.5 mg, and even more particularly from 0.1 mg to 0.25 mg isemployed. The actual amount required varies from compound to compoundbut is an amount which is insufficient to inhibit ovulation, but whichis nevertheless sufficient to maintain adequate antiprogestationaleffects that will prevent nidation from occurring and that will producemenstrual bleeding in fertile female women. In the case of asubcutaneous, depot preparation or medicated intrauterine device,amounts up to 3.0 grams of the active ingredient can be administeredonce or twice a year.

The compoundsof the present invention are administered in various dosageunit forms such as tablets, capsules, powders, granules, oral solutionsor suspensions, sterile solutions or suspensions for parenteral use,sublingual and intrabuccal preparations, aerosols and sprays'forinhalation and insufflation therapy, creams, lotions, and ointments fortopical use, intravaginal and rectal suppositories, vaginal rings,impregnated with the active ingredient, intrauterine devices,subcutaneous and intramuscular implants, depot preparations and asfurther illustrated in the Examples.

In the preparation of solid compositions such as tablets, the principalactive ingredient is mixed with conventional pharmaceutical excipientssuch as gelatin. starches, lactose, magnesium stearate, talc, acacia,di-- calcium phosphate and functionally similar materials. Tablets canbe laminated coated or otherwise compounded to provide for a prolongedor delayed action or to release a predetermined successive amount ofmedication. Capsules are prepared by mixing the steroid with an inertpharmaceutical filler or diluent and filled in either hard gelatincapsules or machine encapsulated soft gelatin capsules. Syrups orelixirs can contain the active ingredients together with sucrose orother sweetening agent, methyl and propyl parabens as preservatives, andsuitable color and flavoring agents.

Parenteral fluid dosage forms are prepared by utilizing the activeingredient in a sterile liquid vehicle, the preferred vehicle beingwater or saline solution. The parenteral formulations include thoseadministerable by a jet gun. Compositions having the desired clarity,stability and adaptability for parenteral use are obtained by dissolvingfrom about 0.1 milligram to about 3 grams of the active ingredient in avehicle consisting of a mixture of nonvolatile. liquid polyethyleneglycols which are soluble in water and organic liquids. and which havemolecular weight ranging from about 200 to about 1500. The solutions mayadvantageously contain suspending agents, such as sodiumcarboxymethylcellulose, methylcellulose, polyvinylpyrrolidone orpolyvinyl alcohol. Additionally, they may contain bactericidal andfungicidal agents, as for example, parabens, benzyl alcohol, phenol orthimerosal. If desired, isotonic agents can be included such as sugar orsodium chloride, as well as local anesthetics, stabilizing or bufferingagents. In order to further enhance stability, the parenteralcompositions may be frozen after filling and water removed byfreeze-drying techniques well known in the art. Such dry, lyophilizedpowders are generally reconstituted immediately prior to use.

Topical ointments are prepared by dispensing the active ingredient in asuitable ointment base such as petrolatum, lanolin, polyethylene glycolsor mixtures thereof. Generally, the steroid is finely divided by millingor grinding. Creams and lotions are prepared by dispersing the activeingredient in an oily phase and subsequently forming an emulsionthereof.

The active ingredient can also be compressed into pellets and implantedsubcutaneously or intramuscularly as a depot injection or implant.Implantation re sults in a slow but predetermined rate of absorptionfrom the site of implantation. Such implants may additionally employinert materials, as for example, biodegradable polymers and syntheticsilicone polymer rubbers.

The instant compounds can also be mixed with a silicone polymer andmolded in the form of cylindrical rings, loops, coils, petals or othershapes which can be inserted directly into the uterus. The activeingredient diffuses through the permeable polymeric material at arelatively slow and constant rate thereby enabling itsantiprogestational effects to be available directly at the site ofsevere activity.

The following preparation and examples are illustrative of the novelcompounds of the present invention, their preparation, compositions anduse in accordance with the above.

EXAMPLE 1 3,7a-Dimethylestra-3,5-dien-173-01 acetate A solution of 50 ml(0.8 mole) of 1.6M methyllithium in ether is added to 4.7 g (0.015 mole)17B- hydroxy-7a-methylestr-4-en-3-one in 150 ml tetrahydrofuran over aperiod of 10 minutes and the resultant solution is stirred for 3 hoursat room temperature. The mixture is poured onto an aqueous ammoniumchloride solution and the organic layer washed well with water, driedand evaporated under reduced pressure. The residual oil is stirred for aperiod of sixteen hours in 50 ml pyridine and 50 ml acetic anhydride andpoured onto an ice/water mixture and extracted with ether. The etherextract is dried over magnesium sulfate and filtered. Additional etheris added to bring the total volume to 300 m1 and the solution cooled toC. Triethylamine 1.63 g (0.016 mole) and phosphorous oxychloride 2.45 g(0.016 mole) are added all at once and the resultant mixture is stirredfor 30 minutes at 0C. The suspension is filtered and the filtrate washedwell with water, dried over magnesium sulfate and distilled to dryness.The residue is purified by chromatography on a silica gel column,eluting the column with methylene chloride and recrystallizing from ahexane solution to yield 3,7a-dimethylestra-3,S-dien-l 78-01, acetate,m.p. l14-115C..

Anal. Calcd. for C H O C,80.43; H982. Found: C,80.58; H.967.

EXAMPLE 1 l 7a-Methyl-3-phenylestra-3,5-dien-17,8-01

A solution of 7a-methyl-l9-nortestosterone 2.8 g 10 m mole) in a mixtureof 50 ml of tetrahydrofuran and ml of ether is treated with 24 ml of asolution of 25% phenyl magnesium chloride in C 11,, (24 ml). After 1hour, the reaction is poured onto aqueous ammonium chloride. The benzeneextract is washed with water, dried over magnesium sulfate and taken todryness under reduced pressure. The diol so obtained is dehydrated byrefluxing for 1 hour in an acetone (250 ml)- 1072 aqueous hydrochloricacid (15 ml) solution. This solution is concentrated under reducedpressure and chromatographed on a silica gel column (50 g) eluting withbenzene-5% acetone and crystallizing from aqueous methanol to yield7a-methyl-3-phenylestra-3,5- dien-l7B-ol, (2.0 g 57.5%). m.p. 148C., ir(KBr), 3470, 1590 (m) cm; uv max (EtOH) 228 (6 10,300), (6 9,700), 287nm (6 16,400); nmr (CDCl;,) 5 0.78 (S, C ,,H 0.88 1d, J 71-12,C7ozCH,,), 5.625.78 (m .05, C,,H), 6.60 (br s, 0.5, C,-*H). 7.17-7.67(m, 5, AR-H.)

Anal. Calcd. for C H O: C, 86.15; H. 9.25. Found: C, 86.20; H. 9.19.

EXAMPLE Ill 3,4,7a-Trimethylandrosta-3,S-dien- 1 73-01 A solution of4,7a-dimethyl-17B-hydroxyandrost-4- en-3-one, 1.5 g (4.75 m mole) in amixture of 50 m1 ether and 30 ml tetrahydrofuran is treated with 30 mlof 1.6 M etheral methyl lithium. After 1.5 hours, the mixture is pouredonto a saturated aqueous ammonium chloride solution and diluted withbenzene. The organic layer is separated, dried over magnesium sulfateand concentrated in vacuo resulting in the formation of3,4,7a-trimethylandrost-4-ene-3,l7,8-diol as a glass. This material isdissolved in 250 ml of acetone, treated with 15 ml ofa 10% aqueoushydrochloric acid solution and heated at its reflux temperature for 0.5hour. The solution is concentrated in vacuo, thhe residue dissolved inbenzene, the benzene solution is washed with water, ,dried overmagnesium sulfate and concentrated in vacuo. The residue is purified bychromatography on a silica gel column (60 g), eluting with C H -5%acetone and crystallizing from an aqueous acetone to give3,4,7a-trimethylandrosta-3,5-dien-17,8-01, m.p. -160C.; ir (KBr) 3480,1630(w) cm; uv max (EtOH) 236 (6 18,300), 243 nm (e 18,900); nmr

EXAMPLE 1V 3-Chloro-7a-methylandrosta-3 .S-dien- 1 713-01 acetate7a-methyltestosterone acetate, 4.4 g (12.7 mole) in 25 ml of acetic acidis treated with phosphorous trichloride, (2 ml). After 18 hours, thesolid is filtered and crystallized from acetone to yield 3-chloro-7amethylandrosta-3,5-dien-l7,8-01 acetate, (1.0 g 21.6%), m.p. 178-180C.

Anal. Calcd. for C H ClO C, 72.79; H, 8.61; Cl, 9.78. Found: C, 72.60;H, 8.68; Cl, 9.75.

EXAMPLE V 3,7a,17a-Trimethylandrosta-3,S-dien-17B-ol A solution of 1.4 g3,7a-dimethylandrosta-3,5-dienl7-one (4.7 m mole) is heated with 15 mlof ethereal 1.6 M. methyl lithium. After 1 hour, the mixture is pouredonto a saturated aqueous ammonium chloride solution and diluted withbenzene. The organic layer is separated, dried over magnesium sulfateand concentrated in vacuum. The residue is chromatographed on a silicagel column and crystallized from aqueous acetone to yield 3,704,l7a-trimethylandrosta-3,5-dien- 17,8-01 (0.8 g, 54.2%) m.p. ll8-l2lC.;ir (KBr) 3,360,1620(w)cm;uv max (EtOH) 232 (6 23,200), 238 (6 24,500),248 nm (6 15,700); nmr(CDCl31 6 0.78, (Vzd, C7a-CH 0.88 (S, C CH3), 1.72(S, C,-CH, 5.26 (d, 1, J Hz, C,,H), 5.67 s, 1, C -H).

Anal. Calcd. for C H O: C, 84.02; H, 10.90. Found: C, 83.54; H, 10.96.

EXAMPLE VI 7a-Methylandrosta-3,S-diene-1 lB,l7,B-diol To a stirredsuspension of 7a-methylandrosta-4-ene- 3,11,17-trione, 10.5 g (34.4 mmole) is added 3.0 g of lithium aluminum hydride in tetrahydrofuran 100ml). After 18 hours, the excess hydride is decomposed by the cautiousaddition of water. Magnesium sulfate is added, the insoluble saltsfiltered and solution distilled to dryness under vacuum. The resultingtriol is dissolved in a mixture of 500 ml of acetone and 50 m1 of ahydrochloric acid solution and the solution refluxed for 1 hour. Thesolution is concentrated, diluted with water and the resulting solidfiltered and crystallized from aqueous methanol to yield 704-methylandrosta-3,S-diene-l 1,8,17B-diol, m.p. l78-l80C.; ir (KBr) 3,440,1650 (m) cm; uv max (EtOH) 229 (6 18,700), 236 (6 20,900), 245 (e13,900); nmr (CDCl 5 0.86 (d. J-6.5 Hz, C70: CH 1.03 (S, C,,H=;). 1.26(S, C -H 5.32 (d, l, J 41-12, C,,H), 5.69-5.85 (m, l, C -H) 5.99 (d, l,J 10Hz, C -H).

Anal. Calcd. for C H O AH O: C, 77.08; H, 9.87. Found: C, 77.21; H,9.86.

EXAMPLE V11 3-Chloro-7a-methylandrosta-3,S-dien-175-01 A solution of3-chloro-7a-methylandrosta-3,S-dien- 17,8-01 acetate, 3 g (8.29 m mole)in 100 ml of methanol and 10 ml of a 10% aqueous NaOH solution areheated at the reflux temperature for 4 hours and poured into ice water.The solid is filtered, washed well with water and crystallized twicefrom an aqueous acetone solution to yield3-chloro-7a-methylandrosta-3,5- dien-l7B-ol (1.2 g, 45.2%), m.p.178-180C.

Anal. Calcd. for C ,,H ClO: C, 74.84; H, 9.11; Cl, 11.06. Found: C,74.47; H, 9.22; Cl, 10.70.

EXAMPLE Vlll 7,8-Methylandrosta-3,S-diene-1 1,8,17,8-dio1 To a stirredsuspension of lithium aluminum hydride 1.0 g in tetrahydrofuran (300 ml)is added 73- methylandrost-4-ene-3,l 1,17-trione 3.4 g 10.8 m mole).After 18 hours at room temperature, the excess hydride is decomposed bythe cautious addition of water. Magnesium sulfate is added, the saltsfiltered and the solution distilled to dryness under vacuum. Theresulting triol is dehydrated in a mixture of refluxing 400 ml ofacetone and 30 ml ofa 10% aqueous hydrochloric acid solution. After 30minutes, the solution is concentrated, poured onto water and the solidfiltered. The crude diene so obtained is chromatographed in a silica gelcolumn, eluting with a benzene/15% acetone mixture. The eluate isevaporated to dryness in vacuum and the residue is crystallized from amixture of etherhexane to yield 7,8-methylandrosta-3,S-diene-l 1,8,17,8-diol, m.p. l35-l45C. (dec); ir (KBr) 3,590, 3,420, 1,645 (w) cm; uv max(EtOH) 223 (6 17,400), 236 (6 19,700), 244 HIT1( l3,600)nmr(CDCl )6 1.05(S, C,,,H;,), 1.13 /zd, C7,8CHZ), 1.17 (S, C -H 5.19 (d, l, J =4.5Hz,C,,-H), 5.68-5.84 (m, l. C;,-H 5.98 (ABXq, l, JAB =10Hz,JBX 1.5 Hz,C,H).

Anal. Calcd. for C ll-1300 C, 79.42; H. 10.00. Found: C, 78.93. H.10.30.

EXAMPLE lX 7a-Methylandrosta-3,5-dien-17,801

A stirred suspension of 1.1 g oflithium aluminum hydride intetrahydrofuran 150 ml) is treated with a solution of7oz-methyltestosterone. After 18 hours. the excess hydride is decomposedby the cautious addition of water, magnesium sulfate is added, the saltsfiltered and the filtrate distilled to dryness under vacuum. The residueis dissolved in acetone (500 ml), diluted with 50 ml of a 10% aqueoushydrochloric acid solution and the solution refluxed for a period of 30minutes. The solution is concentrated and the residue diluted withwater. The resulting solid is filtered, washed with H O, dried andrecrystallized from aqueous acetone to yield7amethyl-androsta-3,S-diene-l7,8-01, m.p. 142-l44C., ir (KBr) 3340, 1645(w) cm, uv max (EtOH) 223 (6 19,400), 236 (6 21,200), 244 nm (e 13,600);nmr (CDCl;,) 6 0.78 (S, C ,,H3), 0.88 (/2d, C7a-CH 0.98 (S, C, H3), 5.35(cl, 1, J 5H2, C H), 5.53-5.72 (m, l, C -H), 5.92 (4, l, J =10 Hz, C-H).

Anal. Calcd. for C H O: C, 83.86; H, 10.56. Found: C, 83.66; H, 10.57.

EXAMPLE X 7,8-Methylandrosta-3 ,5-dien-l 73-01 A solution of 3.02 g of7,8-methyltestosterone (10 m mole) in m1 of tetrahydrofuran is added toa stirred suspension of 0.4 g lithium aluminum hydride in 200 ml oftetrahydrofuran. After stirring at room temperature overnight, theexcess hydride is cautiously decomposed with water. The inorganic saltsare removed by filtration and the filtrate is concentrated to give 73-methylandrost-4-ene-3,l7B-diol as a viscous liquid. This residue isdissolved in 450 ml of acetone, treated with a 10% aqueous hydrochloricacid solution and heated at its reflux temperature for 1 hour. Thesolution is concentrated in vacuum, diluted with water and the solidwhich forms is filtered, dissolved in benzene and purified bychromatography on a silica gel column. Concentration of the eluate andcrystallization from aqueous acetone results in the formation of 7B-methylandrosta-3,5-dien-17,8-01, m.p. 159162C.; has the followingspectral properties: ir (KBr) 3420, 1650 (w), 1050 865 cm: uv max (EtOH)227 (e 20,900), 235 (6 23,400), 243 nm (6 15.300). nmr (CDC1 6 0.79 (S,C,,,-H 0.92 (S,C 9H;1). 1.03 (d, J 7Hz,C7,B--CH 5.19 (d, l, J 3H2,C,,-H), 5.635.82(m.1.C;,H), 5.97 (D, J 10Hz. C -H).

Anal. Calcd. for C- H Oz C, 83.86; H, 10.56. Found: C, 84.03: H, 10.70.

EXAMPLE X1 3,7oz-Dimethylandrosta-3,S-diene-l 18,1 7,8diol A mixture of1 13,17B-dihydroxy-7a-methyltestosterone, 8.2 g (25.8 m mole) intetrahydrofuran is treated with 120 ml of ethereal 1.6 M methyl lithium.After 4 hours, the reaction mixture is poured onto aqueous ammoniumchloride and benzene added. The organic layer is washed with water,dried over magnesium sulfate and concentrated under vacuum. Theresulting triol is dehydrated in a mixture of 50 ml of acetone and 50 mlof a 10% aqueous hydrochloric acid solution by refluxing for 1 hour. Theresulting solution is concentrated and diluted with water. The solidwhich forms is filtered and purified by chromatography on a silica gelcolumn, eluting with a mixture of benzene/10% acetone. The eluate isconcentrated to dryness in vacuo and the residue crystallized fromaqueous acetone to yield 3,7a-dimethylandrosta-3,S-dien-l 1,8,17B-diol,m.p. 199203C.; ir (KBr) 3,540, 3,480, 1,625, uv max (EtOH) 232 (e22,100), 238 (e 23,900), 248 nm (6 15,600;) nmr (CDCl:;) 8 0.82 (d, J6.5 Hz, C7a-CH 100 (S, C, H 1.22 (S, C H 1.73 (S, C CH 5.13 (d, l, J 4HC H), 5.63 (S, l, C,-H).

Anal. Calcd. for C H O C, 79.70; H, Found: C, 80.02; H, 10.41.

EXAMPLE XII 104,3 ,7a-Trimethylandrosta-3,S-dien-173-01 A stirredsolution of 1a,7a-dimethyltestosterone, 1.7 g (5.38 m mole) in 130 mltetrahydrofuran is treated with ml of ethereal 1.85 M methyl lithium.After minutes, the reaction is poured onto saturated aqueous ammoniumchloride, diluted with ether and the organic layer separated, dried overmagnesium sulfate and concentrated under vacuum. The diol so obtained isrefluxed in a mixture of 250 ml of acetone and 50 ml of a 10% aqueoushydrochloric acid solution for a period of one hour. The reactionmixture is concentrated, poured into water and filtered. The crude dieneso obtained is chromatographed on a silica gel column (60 g) elutingwith a mixture of benzene containing 5% acetone. The eluate isevaporated to dryness in vacuo and crystallized from aqueous acetone toyield la,3,7atrimethylandrosta-3,5-dien-1713-01, (0.8 g, 47.3%) m.p.l6l165C.; ir (KBr) 3480, 1630 (w) cm; uv max (EtOH; 232 (6 23,300), 238(6 25,000), 247 nm (6 16,000); nmr (CDC1 8 0.78 (S, C -H 0.88 /zd, C1aCHC7a-CH 1.73 (S, C CH 3.67 5.28 (d, l, J 5H2, C -H), 5.68 (S, l, C -H).

Anal. Calcd. for C H O: C, 84.02; H, 10.90. Found: C. 83.96; H, 11.13.

EXAMPLE X111 701,17a-Dimethylandrosta-3,S-dien-1 7-01 A solution of7a-mcthylandrosta-3.S-dien-l7-one 2.84 g 10 m mole), in a mixture of mlof ether and 50 ml of tetrahydrofuran is treated with 40 ml of 1.6 Methereal methyl lithium (40 ml). After 1 hour, the mixture is pouredonto saturated aqueous ammonium sulfate, diluted with benzene and theorganic layer separate, dried over magnesium sulfate and concentrated invacuum. The residue is dissolved in benzene and purified bychromatography on a silica gel column. The eluate is evaporated todryness in vacuo, and crystallized from benzene. The70,17a-dimethylandrosta-3,S-dien- 175-01 so obtained, m.p. 7C. has thefollowing properties: ir (KBr) 3420, 1645 (w), 1625 (2), 1150, 860 cm;uv max (EtOH) 228 (6 14,600) 236 (e 15,900), 244 nm (6 10.600); nmr(CDCl 6 0.78 (M d, C7aCH 0.91 (S, C,,,H,,), 1.01 (S, C, -H 1.23 (S, C CH5.41 (d, C,,H), 5.60-5.78 (m, C ,H), 5.98 (d, C H).

Anal. Calcd. for C H O: C, 83.94; H, 10.73 Found: C, 83.76; H, 10.91.

EXAMPLE XlV 7a-Methyl-3-phenylandrosta-3,S-dicn-17B-ol A solution of7a-methyltestosterone, 3.8 g (12.6 m mole) in a mixture of 100 m1 ofether and 50 ml of tetrahydrofuran is treated with 20 ml of 3 M etherealphenyl magnesium chloride (60 m mole). After 2'hours, the mixture ispoured onto a mixture of ice, water and concentrated hydrochloric acid,diluted with ether and the organic layer is separated, dried overmagnesium sulfate and concentrated under vacuum to yield 701-methyl-3-phenylandrost-4-ene-3,l7B-diol as a solid. This residue isdissolved in acetone, diluted with a 10% aqueous hydrochloric acidsolution and boiled on a steam bath for about 30 minutes. The cooledreaction mixture is diluted with water and extracted with ether. Thecombined organic extracts are dried over magnesium sulfate, filtered andconcentrated in vacuum to yield a solid which is purified by dissolvingin benzene and purifying on a silica gel chromatographic column. Theeluate is evaporated to dryness in vacuo and crystallized from aqueousacetone solution to yield 7amethyl-3-phenylandrosta-3,S-dien-17B-olhaving the following properties: ir (KBr) 3460, 1640 (w), 1595 (w), 755,690 cm; uv max (EtOH) 220 (6 10,200), 228 (5 10,900). 234 nm (6 9.500);nrm (CDCl 8 0.80 (S, C, H 0.93 /zd, C7aC1-1 1.03 (S, C H 5.60 (d, C -H),6.47 (s, C H), 7.17-7.65 (m, ArH 5).

Anal. Calcd. for C H O: C, 86.13; H, 9.45 Found: C, 85.85; H, 9.46.

EXAMPLE XV 3-Butyl-7oz-methylandrosta-3,S-dien- 178-01 A solution of7oz-methyltestosterone 2.4 g (7.95 m mole) m1 of tetrahydrofuran istreated with 40 ml ofa 15% butyl lithium solution in hexane. After 1hour, the mixture is poured onto an aqueous ammonium chloride solutiondiluted with ether. The organic layer is washed with water, dried overmagnesium sulfate and the solvent removed under vacuum. The crude diolso obtained is dehydrated by refluxing in 20 ml of acetone containing 20ml of a aqueous hydrochloric acid solution. The solution isconcentrated, poured into water, and filtered. The crude dicne ischromatographed on a silica gel chromatographic column (50 g), elutingwith a benzene 5% acetone solution. The eluate is evaporated to drynessand crystallized from aqueous acetone to give3-butyl-7a-methylandrosta-3,5-dien- 17B-ol: (1.0 g, 37.9%), m.p.l21-124C.; ir (KBr) 3470, 1650 (w), 1620 (w) cm; uv max (EtOH) 233 (623,200), 242 (a 25,400), 249 nm (6 16,500); nrm (CDCl;,) 8 0.78 (S, C H0.89 /2d, C7 xCH 0.95 (S, C -H 5.78 (d, l. J 5H2, C,,-H), 5.67 (S, 1, C-H).

Anal. Calcd. for C H O: C, 84.15; H, 11.18. Found: C, 84.39; H, 11.42.

EXAMPLE XVI 3,7B-Dimethylandrosta-3,5-dien-17,8-01

A solution of 7B-methyltestosterone, 4.53 g m mole) in a mixture of 200ml of ether and 125 ml of tetrahydrofuran is treated with 41 ml of 1.6 Methereal methyl lithium. After standing for 30 minutes, the mixture ispoured into a saturated aqueous ammonium chloride solution and dilutedwith ether. The aqueous layer is separated and washed with ether. Thecombined organic layers are backwashed with a saturated ammoniumchloride solution, dried over magnesium sulfate and concentrated invacuum to yield 3,7,8-dimethylandrost-4-ene-3, 17B-diol as a yellow,viscous liquid. This material is dissolved in 500 ml of acetone, treatedwith 50 ml ofa 10% aqueous hydrochloric acid solution and heated at itsreflux temperature for a period of 1 hour. The solution is concentratedin vacuum and the residue twice extracted with methylene chloride. Thecombined extracts are washed with water, dried over magnesium sulfate,treated with charcoal, filtered and concentrated under vacuum to anorange liquid which is dissolved in benzene and purified bychromatography on a silica gel chromatographic column. The eluate isevaporated to dryness and recrystalizeed from an aqueous acetone toyield 3,713- dimethy1androsta-3,5-dien-175-01, m.p. 132-134C., ir (KBr)3340, 1635 (w), 1055, 885 cm; uv max (EtOH) 231 (6 22,800), 238 (625,200), 247 nm (6 16,700); nmr (CDCI 8 0.78 (s, C H 0.90 (d, C H 1.01(d, C7,B-CH 1.73 (s, C CH 5.10 (d, C H), 5.73 (s, C H).

Anal. Calcd for C H O: C, 83.94; H, 10.73. Found: C, 84.07; H, 10.87.

EXAMPLE XVII 3,7a-Dimethy1androsta-3,S-dien-17-one A solution of3,7a-dimethylandostra-3,S-dien-17B- 0], 4.0 g (13.3 m mole) in a mixtureof ml benzene and 20 m1 dimethylsulfoxide, containing 1.0 ml of pyridineand 0.5 ml of trifluoroacetic acid is treated with v 8.35 g ofdicyclohexyl carbodiimide and stirred for a period of 3 hours. Themixture is diluted with 100 ml of ethyl acetate and treated with 5.5 gof oxalic acid in 22 m1 of methanol. After 15 minutes, the solid isfiltered and washed with ethyl acetate. The combined filtrate and washis extracted with water, dried over magnesium sulfate and concentratedin vacuum. The residue is purified by chromatography on a silica gelcolumn, the eluate evaporated to dryness and the residue crystallizedfrom an aqueous acetone solution to yield3,7a-dimethylandr0sta-3,5-dien-17-one, m.p. 149l52C., ir (KBr) 1730,1630 (w) cm; uv max (McOH) 232 (6 22,200), 238 (e 23,500), 247 (a15.700); nmr (CDCl 5 0.89 (d, J 7H2, C7aCH 0.92 (s, C,,,H;,;, 0.98 (S.l9 'H3), 1.74 (s. C CH 5.33 (d, l, .I 5 Hz, C,,H), 5.73 (s, l, C ,H).

Anal. Calcd. for Cull I300: C. 84.51; H. 10.13. Found: C, 84.28; H,10.30.

EXAMPLE XVIII 3 ,7a-Dimethylandrosta-3,S-dien-1701-01 A solution of7a-methyltestosterone, 6.04 g (20 m mole) in a mixture of 150 ml oftetrahydrofuran and 200 ml of ether is treated with ml of a 1.6 M.ethereal methyl lithium solution. After 30 minutes, the mixture ispoured into a saturated ammonium chloride solution and the organic layeris separated, washed with a saturated aqueous ammonium chloridesolution, dried and concentrated to dryness. The residue is dissolved in500 ml of acetone which is diluted with a 10% aqueous hydrochloricsolution and heated at its reflux temperature for 1 hour. The cooledsolution is concentrated and the residue is diluted with water. Theresulting solid is filtered, washed with water, dried andchromatographed on a silica gel column (200 g), eluting with a mixtureof benzene-5% acetone. The eluate is evaporated to dryness andcrystallized from aqueous acetone to yield3,7a-dimethylandrosta-3,5-dien-17B- ol, m.p.162166C.;ir(KBr)3500,1630(w)cm";uv max (EtOH), 232 (6 21,800), 238 (524,000), 247 nm (6 15,400 NMR coon a 0.78 (s, 3, C ,,H 0.88 /zd, C7aCH0.97 (s, C -H 1.73 (s, C Cl-1 5.32 (d, 1, J 4.5Hz, C H), 5.73 (s, l,

Anal. Calcd. for C H O: C, 83.94; H, 10.73. Found: C, 83.96; H, 10.79.

EXAMPLE XIX 1a,7,8-Dimethylandrosta-3,S-dienl 7,8-01

A solution of l01,75-dimethyltestosterone, 1.5 g (4.75 m mole) intetrahydrofuran ml) is added to a stirred suspension of lithium aluminumhydride in 200 m1 of tetrahydrofuran. After standing for a period of 18hours, water is added to the reaction mixture. The salts are removed byfiltration, the filtrate is dried over magnesium sulfate and the solventremoved under vacuum. The residue is dehydrated in 300 ml of refluxingacetone which contains 50 m1 ofa 10% aqueous hydrochloric acid solution.The solution is concentrated, diluted with water and filtered. The solidis purified by chromatography on a silica gel column (50 g), elutingwith a mixture of benzene 5% acetone. The eluate is evaporated todryness and crystallized from aqueous acetone to yieldl0:,7B-dimethylandrosta-3,S-dien-l 7B- 0], m.p. l48150C.; ir (KBr) 3360,1645 (w) cm; uv

max (EtOH) 229 (6 20,900), 237 (6 23,200), 246 nm (6 15,200); NMR(CDCl:,) 5 0.68 /d, C7BCH 0.79 (s, C H 0.98 (s, C -H 1.07 (/2d, ClozCH5.23 (d, l, .I 3 Hz, C -H), 5.37-5.62 (m, l, C H), 5.87 (ABX, l, JAB9H2, JBX 3H2,

EXAMPLE XX 3 .7a-Dimethy1- 1 7B-( 2 -tetrahydropyrany1oxy)androsta-3.5-diene diene Phosphorous oxychloride is added to a solutionof 3.- 7a-dimethyl-androsta-3.5-dien-17B-o1 in 2.3- dihydropyran. Afterstanding at room temperature for a period of 72 hours, the solution isdiluted with ether, washed with aqueous sodium carbonate and water,dried over sodium sulfate and evaporated to dryness under vacuum.Crystallization of the residue from hexane results in the formation of3,7oz-dimethyl-17B-(2- tetrahydropyranyloxy)androsta-3,5-diene.

EXAMPLE XXI l3-Ethy1-3,7ot-dimethylgona-3,5-dien-l7B-o1 acetate Etherealmethyl lithium is added to a tetrahydrofuran solution of l3-ethyl-l7B-hydroxy-7a-methy1-4-gonen- 3-one at C. The ice bath is removed andstirring continued for an additional 4 hours. The reaction mixture ispoured onto an aqueous ammonium chloride solution. The ether layer iswashed with water, dried over magnesium sulfate, and evaporated todryness under reduced pressure. The residue so obtained is stirred withacetic anhydride and pyridine overnight to acylate the l7-hydroxy group.The mixture is partially distilled and then diluted with water,extracted with ether and the combined extracts are washed with water,dried and chilled to 0C. Phosphorous oxychloride and triethylamine areadded which form a precipitate instantly. After 30 minutes. thesuspension is filtered. the ether solution washed with water, sodiumbicarbonate, dried over sodium sulfate and evaporated to dryness. Theresidue is chromatographed on a silica gel column, eluting the columnwith methyleneehloride. The eluate is evaporated to dryness and theresidue crystallized from aqueous acetone to yield13-ethy1-3,7adimethy1gona-3,5-dien-17B-o1 acetate.

EXAMPLE XXII 13-Ethyl-7a-methylgona-3.5-dien-l 78-01 A tetrahydrofuransolution of 13-ethyl-l7B-hydroxy- 7a-methyl-4-gonen-3-one is added to astirred suspension of lithium aluminum hydride in tetrahydrofuran atroom temperature. After hours, an aqueous solution of sodium potassiumtartrate is slowly added and the salts removed by filtration. Theorganic filtrate is dried over magnesium sulfate and concentrated undervacuum. The residue so obtained is dissolved in methylene chloride,washed with water, redried over magnesium sulfate and the solventremoved under vacuum. The resulting residue is dissolved in a mixture ofacetoneaqueous 10% hydrochloric acid and refluxed for a period of onehour. After concentrating the solution, it is diluted with water and thesolid filtered. This crude dien obtained thereby is recrystallized fromaqueous acetone to form 13-ethyl-7a-methy1gona-3,5-dien-l 7,8- 0].

EXAMPLE XXIII l3-Ethyl-7a-methylgona-3,S-dien-173-01 propionate Asolution of 13-ethyl-7a-methylgona-3,S-dien-17B- 0! is stirred overnightwith propionic anhydride and pyridine. The solution is poured ontoicewater and ti]- tered. The solid is chromatographed on a silica gelcolumn, eluting with methylene chloride. The eluate is evaporated todryness and crystallized from aqueous acetone to yield13-ethy1-7a-methy1gona-3,5-dien-17B- ol propionate.

EXAMPLE XXIV 17/3-( 1Methoxycyclohexyloxy)-3,7a-dimethylandrosta-3,5-diene The compound3,7a-dimcthylandrosta-3 .5-dien-17B- o1 is dissolved in anhydrousdioxane and treated with pyridine p-toluenesulfonate and cyclohexanonemethyl enolether. Stirring is continued for a period of 3 hours. Thesolvent is removed under vacuum and the residue is crystallized frompentane resulting in the formation of l7B-( l'-methoxycyc1ohexyloxy)-3,7a-dimethy1androsta-3,5-diene.

EXAMPLE XXV 17/3-( 1 'Cyclohexenyloxy)-3,7a-dimethylandrosta-3,5- dieneEXAMPLE XXVI Preparation of a tablet formulation One thousand tabletsfor oral use, each containing 5 mg of13-ethy1-3,7a-dimethy1gona-3,S-dien-175-01 acetate are preparedaccording to the following formulation:

(a) l3-ethyI-3,7a-dimethylgona-3,S-

dien- 1 78-01 acetate 5 (b) Dicalcium phosphate 150 (e) Methylcellulose,U.S.P. l5 cps) 6.5 (d) Talc 20 (e) Calcium stearate 2.5

The l 3-ethy1-3,7a-dimethy1gona-3,S-dien-17,8-01 acetate and dicalciumphosphate are mixed well, granulated with a 7.5% aqueous solution ofmethylcellulose, passed through a No. 8 screen and carefully dried. Thedried granules are passed through a No. 12 screen, blended with talc andcalcium stearate and compressed into tablets.

EXAMPLE XXVII Preparation of a capsule formulation Onethousand two-piecehard gelatin capsules for oral use each containing 10 mg of3,7a-dimethylestra- 3,5-dien-17B-ol acetate are prepared from thefollowing ingredients: 1

(a) 3 .7a-dimethylestra-3 ,5-dien-17/3- ol acetate 10 (b) Lactose,U.S.P. (0) Starch, U.S.P. 10 (d) Talc, U.S.P. y 5 (e) Calcium stearate 1The finely powdered materials are mixed until uniformlyy dispersed andfilled into hard shelled gelatin capsules of the appropriate size.

In a similar fashion one-piece soft gelatin capsules can be prepared inwhich the above formulation can be granulated, slugged or compresseddirectly into a rotary die or plate mold in which the capsule is formed.

Alternatively, the above excipients may be omitted and the activeingredient dispensed as a powder directly into the capsule.

EXAMPLE XXVlll Preparation of a parenteral injectable solution A sterileaqueous suspension suitable for injection is prepared from the followingingredients 7a-Methylandrosta3,S dienl 7Bol l Polyethylene glycol 4000,U.S.P. 3 Sodium chloride 0.9 Polyoxyethylene derivatives of sorbitanmonooleate (TWEEN 80) L'.S.P.

Sodium metahisulfite Methylparaben, U.S.P. Propylparaben. U.S.P.

Water for injection q.s. to 100 ml 0.4 O. l 0. l 8 0.03

( if) (g) (h) EXAMPLE XXIX Preparation of an ointment One thousand gramsof an ointment for topical application containing 0.l% ofl3-ethyl-7oz-methylgona-3,5- dien-l'lB-ol can be prepared from thefollowing ingreclients:

(a) l3-cthyl-7a-methylgona-3 S-dien 173-01 1 (b) Light liquid petrolatum250 (c) Wool fat 200 (d) White petrolatum q.s. ad 1000 The wool fat,white petrolatum and 200 gms of the light liquid petrolatum areliquified and held at 110F. The steroid is mixed with the remainingliquid petrolaturn and passed through a colloid mill. After passingthrough the mill, the mixture is stirred into the melt. The melt ispermitted to cool with continued stirring until congealed.

EXAMPLE xxx Preparation of an intrauterine device A mixture of 1.0 gramof l3ethyl-7oz-methylg0na- 3,5-dien-l7B-ol and 18 grams of syntheticsilicone polymer rubber, Silastic, Dow-Corning Medical Silastic 382elastomer, and 3 drops of stannous octoate are mixed and placed in atoroidal mold. The mold is cured at 40 for 4 hours, cooled, and theelastic toroidal rings so prepared are trimmed of excess polymer.Suitable rings having an outside diameter of 65 mm and weighingapproximately 18 grams each can be prepared in this manner. Optionally,filler such as 10 micron size amorphous silica may be incorporated inthe silicone rubber to control the rate and degree of permeability ofdiffusion.

We claim:

1. A 7-alkyl-3,5-unsaturated steroid having the general formula:

wherein R R R and R are each hydrogen or methyl;

R is selected from the group consisting of hydrogen,

chloro, bromo, lower alkyl having from 1 to 4 carbon atoms, phenyl,halophenyl, hydroxyphenyl, tolyl, and methoxyphenyl;

R is lower alkyl having from 1 to 3 carbon atoms;

R, is selected from the group consisting of CH CHOH and C O;

R is selected from the group consisting of hydrogen, lower alkyl havingfrom 1 to 6 carbon atoms, lower alkenyl and lower alkynyl having from 2to 6 carbon atoms, lower alkenynyl and lower alkadiynyl having from 4 to6 carbon atoms;

R,, is selected from the group consisting of hydrogen,

acyl having from 2 to 12 carbon atoms, 2- tetrahydropyranyl,trimethylsilyl, l-cycloalkenyl having from 5 to 8 carbon atoms, 1-methoxycycloalkyl and l-ethoxycycloalkyl in which the cycloalkyl grouphas from 5 to 8 carbon atoms, and the groups R andOR when taken togetherare oxo or a cyclic acetal; and

R is hydrogen with the proviso that when R and R,

are hydrogen, R R R and R, cannot all be hydrogen at the same time.

2. A compound of claim 1 wherein R is methyl, R

is alpha-methyl and R is hydrogen.

3. A compound of claim 1 which is 3,7a-dimethylestra-3 ,5-dienl 7B-ol.

4. A compound of claim 1 which is 3,7a-dimethylestra-3,5-dien-l7B-ol,acetate.

5. A compound of claim 1 which is 3,7adimethyl-

1. A 7-ALKYL-3,5-UNSATURATED STEROID HAVING THE GENERAL FORMULA:
 2. Acompound of claim 1 wherein R2 is methyl, R5 is alpha-methyl and R7 ishydrogen.
 3. A compound of claim 1 which is 3,7 Alpha-dimethyl-estra-3,5-dien-17 Beta -ol.
 4. A compound of claim 1 which is3,7 Alpha -dimethyl-estra-3,5-dien-17 Beta -ol, acetate.
 5. A compoundof claim 1 which is 3,7 Alpha -dimethyl-androsta-3,5-dien-17 Beta -ol.